Fig. 4

Long-term inhibition of ODC1 in AD creates an Aβ-clearing and neuro-supportive active state. Top-Left: In AD, astrocytes show upregulated autophagy to uptake accumulated amyloid deposits and switch-on the urea cycle along with upregulation of enzyme ODC1, which increases putrescine, GABA, H₂O₂ and ammonia production, causing neurodegeneration and memory impairment. Top-Right: Short-term ODC1 inhibition in AD mouse models blocks the conversion of ornithine to putrescine, increases the flux of the urea cycle, reduces production of putrescine, GABA, H₂O₂ and thereby preventing oxidative stress, neurodegeneration, and memory impairment. These astrocytes can be called Aβ-detoxifying astrocytes (schematics adapted from Ju et al. [4]) Bottom: Long-term inhibition of ODC1 in AD-like astrocytes can improve Aβ plaque clearance and drastically alter the transcriptome of astrocytes, by increasing histone modifications, Nrf2 expression, proBDNF production, protein-associated processes and cellular metabolism. These changes, along with reduced apoptotic signaling, ubiquitination and synaptic pruning-associated genes, resemble the transcriptome of EE active astrocytes and can create a neuro-supportive environment for regeneration (Created using biorender.com)